Schizophrenia is a devastating neuropsychiatric disorder which affects approximately 1% of the population and results in serious disruption in the lives of afflicted individuals and their families. Common symptoms include delusions, conceptual disorganizations and visual or auditory hallucinations, as well as changes in affective behavior. A number of scales for the rating of symptoms and methods for ascertaining the diagnosis have been developed, including the DSM classification by the American Psychiatric Association (Diagnostic and Statistical Manual of Mental Disorders (4th edition), pp. 273-316, 1994), which have attempted to refine the accuracy of clinical diagnosis. However, it is likely that similar symptoms can result from several underlying abnormalities, and diagnosis relying solely on clinical symptoms is difficult and controversial, as well as subjective, time-consuming and costly.
The cause or causes of schizophrenia remain obscure. A defect in dopamine pathways of synaptic neuronal function is a central feature of the most widely held etiopathogenic theory (known as the Dopamine Hypothesis), with recent emphasis on the role of D.sub.4 -type dopamine receptors (Taubes, Science 265:1034-1035, 1994). However, studies to date have failed to identify abnormalities in the basic receptor structure, suggesting that dysfunction may result from an alteration in the dynamic regulation of receptor activity.
Dopamine receptors are members of a large superfamily of G protein-coupled receptors which share a high degree of structural similarity while recognizing a widely divergent array of substances which affect cellular function. Recent advances in the study of these receptors have led to the identification of key locations on the receptors which can modulate their function and which therefore may be sites of malfunction in schizophrenia (Samama et al., J. Biol. Chem. 268:4625-4636, 1993). One such critical location or "hot spot" in the dopamine D.sub.4 receptor is a methionine amino acid residue (Van Tol et al., Nature 350:610-614, 1991).
A number of clinical and metabolic studies have documented altered methionine metabolism in individuals with schizophrenia (Kelsoe et al., J. Neurosci. Res. 8:99-103, 1982; Ismail et al., Biol. Psych. 13:649-660, 1978; Sargent et al., Biol. Psych. 32:1078-1090, 1992). For example, the administration of methionine has been shown to elicit an acute psychotic reaction in persons with schizophrenia but lacks such an effect in normal individuals (Cohen et al., Biol. Psych. 8:209-225, 1974). Conversely, administration of S-adenosylmethionine has been shown to have antidepressant benefits (Kemali et al., Biochemical and Pharmacological Roles of Adenosylmethionine and the Central Nervous System, Pergamon Press, pp. 141-147, 1979).
Recently, these findings have been integrated upon the discovery that methionine residue #313 (human D.sub.4 receptor numbering) of the dopamine D.sub.4 receptor appears to be abnormally modified in schizophrenic individuals (Deth, "Compositions and Methods for Detection of Schizophrenia," WO 96/37780, the whole of which is hereby incorporated by reference herein). Methionine residue #313 is normally modified by the addition of an adenosyl group to its sulfur atom via the action of a methionine adenosyltransferase (MAT) enzyme; however, individuals with schizophrenia are known to be deficient in MAT activity (Carl et al., Biol. Psych. 13:773-776, 1978) and, thus, are expected to possess a lesser amount of the modified form of the dopamine D.sub.4 receptor. This deficiency is evident in a variety of tissues, including brain tissue and blood cells, particularly white blood cells, and is central to the biochemical diagnosis of schizophrenia.